Obesity, and disorders associated with obesity such as diabetes, are a major global health concern. Obesity, which is generally associated with an abnormal accumulation of fat cells, develops when energy intake exceeds energy expenditure. Adipose tissues play an important role in obesity, insulin resistance and diabetes. Two functionally different types of fat tissues are present in mammals: white adipose tissue (WAT), which is the primary site of depot of triglycerides and release of fatty acids, and brown adipose tissue (BAT), which is specialized in thermogenic energy expenditure through the expression of uncoupling protein-1 (UCP-1).
The most commonly known fat cells are white fat cells, also known as white adipose tissue (WAT) cells, which have a thin ring of cytoplasm surrounding a lipid or fat droplet. WAT is found underneath the skin and provides heat insulation, cushioning against shock and jarring, and energy reserves. An average lean person has roughly 20 to 40 billion WAT cells. An obese person can have up to ten times more WAT than the average lean person.
The less common fat cells are the brown fat cells, also known as brown adipose tissue (BAT) cells. Energy expenditure for thermogenesis in BAT serves either to maintain body temperature in the cold or to waste food energy. It has roles in thermal balance and energy balance, and when defective, is usually associated with obesity. BAT is typically atrophied in obese animals. The importance of BAT in overall energy homeostasis is underscored by the finding that ablation of BAT in mice results in severe obesity accompanied by insulin resistance, hyperglycemia, hyperlipidemia, and hypercholesterolemia (Lowell at al., Nature 366(6457):740-2 (1993); Hamann et al., Diabetes. 44(11):1266-73 (1995); Hamann et al., Endocrinology 137(1):21-9 (1996). Increasing the relative proportion and function of BAT may increase whole body energy expenditure, preventing the development of obesity. In fact, the role of BAT as a defense against obesity has been clearly demonstrated through targeted ablation of this tissue in mice and the BAT-less mice become more susceptible to diet-induced obesity, diabetes, and hyperlipidemia (Lowell et al., Nature 366:740-742 (1993); Hamann et al., Endocrinology 137:21-29 (1996).
BAT also features the presence of abundant and large mitochondria (Nedergaard et al., in Brown Adipose Tissue, Trayhurn and Nicholls, Eds. (Edward Arnold, Baltimore, 1986)), which serve as the center site for oxidative phosphorylation, intermediary metabolism, adaptive thermogenesis, generation of reactive oxygen species and apoptosis. In BAT, mitochondrial biogenesis has been long known to accompany brown adipocyte differentiation. During the past decade, it has become increasingly evident that the integrity of mitochondria contribute to a variety of human diseases, including obesity, diabetes, cancer, neurodegeneration, and aging (Duchen, Diabetes 53 (Suppl 1): S96-102 (2004); Taylor and Turnbull, Nat. Rev. Genet. 6:389-402 (2005); Lowell and Shulman, Science 307:384-387 (2005)).
Adipose tissues contain a potential mitotic compartment, which can allow for growth and differentiation of WAT or BAT cells. Adipose tissue can be readily assayed using routine techniques. An exemplary assay for adipose cells is the Oil Red O lipophilic red dye assay. The dye is used to stain neutral lipids in cells. The amount of staining is directly proportional to the amount of lipid in the cell and can be measured spectrophotometrically. The amount of lipid accumulation is determined as a parameter of differentiation. WAT and BAT can be distinguished by routine techniques, e.g., morphologic changes specific to WAT or BAT, or evaluation of WAT-specific or BAT-specific markers. For example, BAT cells can be identified by expression of uncoupling protein (UCP), e.g., UCP-1.
Bone morphogenetic proteins (BMPs) belong to the TGFβ superfamily. BMPs bind to specific type-I and -II serine/threonine kinase receptor complexes, RIa, RIb, and RII, which signal through SMAD proteins or the p38 mitogen-activated protein kinase (MAPK). The BMPs are important regulators of key events in many aspects of tissue development and morphogenesis, including the processes of bone formation during embryogenesis, postnatal growth, remodeling and regeneration of the skeleton. Localization studies in both human and mouse tissues have demonstrated high levels of mRNA expression and protein synthesis for various BMPs in adipose, heart, lung, small intestine, limb bud and teeth.
Several BMPs have been implicated in early skeletal development, including BMP-2,-4, -5, -7, -14 (CDMP-1/GDF-5). Other members, such as BMP-3, -6, -7 and -13 (CDMP-2/GDF-6) may be involved in later stages of skeletal formation.